WO1993018748A1 - Compositions contenant un vehicule d'administration de medicament en suspension dans un liquide fluore non aqueux - Google Patents

Compositions contenant un vehicule d'administration de medicament en suspension dans un liquide fluore non aqueux Download PDF

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Publication number
WO1993018748A1
WO1993018748A1 PCT/US1993/002500 US9302500W WO9318748A1 WO 1993018748 A1 WO1993018748 A1 WO 1993018748A1 US 9302500 W US9302500 W US 9302500W WO 9318748 A1 WO9318748 A1 WO 9318748A1
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Prior art keywords
pharmaceutical composition
group
perfluorocarbon
perfluoro
amended
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PCT/US1993/002500
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English (en)
Inventor
David Louis Meadows
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Allergan, Inc.
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Publication of WO1993018748A1 publication Critical patent/WO1993018748A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0026—Blood substitute; Oxygen transporting formulations; Plasma extender
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/02—Halogenated hydrocarbons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/02—Halogenated hydrocarbons
    • A61K31/025—Halogenated hydrocarbons carbocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present invention relates in general to nonaqueous pharmaceutical compositions intended for use in aqueous physiological systems. More particularly, the present invention is directed to pharmaceutical compositions formed of drug containing microparticulate or microcapsule delivery vehicles suspended in perfluorocarbons or fluorinated silicone liquids.
  • the pharmaceutical compositions of the present invention possess unexpectedly superior shelf-lives, increased bioavailabuity, prolonged drug delivery profiles and may be configured for convenient multi-dose administration through common routes of pharmaceutical administration including advantageously small volume drop installation administration.
  • drug delivery vehicles are formed as aqueous carriers, gels, polymeric material inserts or particulates incorporating a pharmaceutical compound.
  • drug delivery vehicles may be delivered to the target site through a variety of known routes of administration.
  • aqueous based drug delivery solutions may be ingested, injected, inhaled, or applied directly to the skin or mucus membranes as drops, mists, or the like.
  • gels and ointments are better suited to direct topical application due to their relatively high viscosities.
  • solid polymeric inserts must be physically inserted or affixed to the target site.
  • a particularly unique target site for pharmaceutical compounds is the ocular environment surrounding the surface of the eye.
  • Aqueous solutions, gels and solid inserts have all been utilized to deliver ocular drugs as the controlled delivery rate characteristics of such known delivery vehicles make them well suited for delivering therapeutic and diagnostic compounds to the ocular environment.
  • tear turnover and drainage through the lacrimal system quickly remove a major portion of any compound administered as a drop to the eye so that only a small fraction of the original dosage remains in the eye long enough to be of therapeutic impact.
  • unnecessarily high liquid dose volume inherent in water and oil based delivery systems result inefficient use of drug delivery compositions.
  • compositions such as ointments, gels or inserts which remain in the eye and gradually release their diagnostic or therapeutic drugs into the ocular environment reduce the need for repeated administrations of the drug to the eye.
  • microparticulates are formed of a drug containing polymer matrix formed in particles ranging from tens to hundreds of microns in diameter. The polymer matrix may be erodible to release the incorporated drug at the target site as the matrix gradually breaks down.
  • microparticulates may be formed of non- erodible polymers from which the incorporated drug simply diffuses out of and into the target tissue.
  • Microcapsules are comparably sized particles formed of a polymer shell encapsulating the desired pharmaceutical compound.
  • the shell of microcapsules may also be composed of either erodible or non-erodible polymers.
  • liquid carrier medium which is physically and chemically compatible with both the polymer of the drug delivery vehicle and the incorporated therapeutic or diagnostic compound as well as the intended physiologic environment.
  • the liquid carrier of choice is a sterile water solution of the appropriate pH and os olality.
  • a problem with suspending micro ⁇ particles or microcapsules in aqueous carriers targeted for an aqueous physiological environment is that invariably the incorporated pharmaceutical compound will leach into the aqueous carrier prior to administration. This results in a significant loss of pharmaceutical activity at the site of action as the leached drug contained in the aqueous carrier will be flushed from the target site relatively rapidly.
  • compositions con ⁇ taining drug delivery vehicles utilizing a polymer or drug which is unstable or labile in an aqueous environment cannot be stored for extended lengths of time in their aqueous carriers without significant chemical changes occurring.
  • a significant number of the polymers which are currently being utilized as microparticulate drug delivery vehicles are hydrolytically labile. This characteristic is central to the ability of the polymer matrix to slowly disintegrate and release the drug incorporated in the polymer matrix into the aqueous physiological environment. Since the polymer systems exhibiting hydrolytic instability cannot be stored in aqueous vehicles, they must be stored in a dry state and suspended in the aqueous carrier immediately prior to their administration to the target site. This is a time consuming and burdensome inconvenience to the end user.
  • a related drawback associated with the ophthalmic drop instillation delivery of pharmaceuticals incorporated in water or oil carrier systems is that conventional small volume droppers have relatively limited delivery volumes restricted to drop sizes that may interfere with vision or be uncomfortable to the user. This is because the density and surface tension characteristics of the typical water and oil based systems do not allow for the practical delivery of less than 35 ⁇ l volumes. Thus, because the eye tear film can accommodate only about a 7 ⁇ l volume of liquid, when amounts greater than this are delivered to the eye the excess liquid will disrupt the tear film and may be rapidly blinked away. This results in the inefficient and costly loss of both liquid carrier and pharmaceutical agent.
  • compositions which will effectively deliver water labile or poorly soluble therapeutic or diagnostic pharmaceutical compounds to aqueous physiological target sites through a wide variety of administrative routes including ingestion, injection, inhalation, topical application, sprays, mists, drops and the like. It is a further object of the present invention to provide pharmaceutical compositions for delivering water labile or poorly soluble therapeutic or diagnostic pharmaceutical compounds which exhibit improved shelf-life and stability.
  • the present invention accomplishes these and other objectives by providing advantageous pharmaceutical compositions formed of drug delivery vehicles suspended in nonaqueous liquid carriers for low dose volume delivery.
  • the pharmaceutical compositions of the present invention have improved bioavailabuity, provide efficient delivery of drugs in the form of low dose volumes and possess long shelf-lives with retained pharmaceutical activity and may be packaged in multi-dose configurations. Additionally, they can be formulated to stably incorporate hydrolytically labile drugs and polymers and may be administered to intended target sites through any available route of administration including small volume drop instillation methods. Unlike prior art drug delivery systems, the pharmaceutical compositions of the present invention can be delivered in dose volumes of less than 10 ⁇ l, resulting in improved drug delivery efficiency and increased bioavailabuity.
  • low volume pharmaceutical compositions are preferably formed from a perfluorocarbon or fluorinated silicone liquid carrier and at least one drug delivery vehicle incorporating the desired therapeutic or diagnostic compounds. It is also contemplated as being within the scope of the present invention to form the drug delivery vehicle of polymeric particulates suspended in nonaqueous liquid carriers wherein the polymeric drug delivery vehicles incorporate a pharmaceutically effective amount of the desired therapeutic or diagnostic compounds.
  • the polymeric drug delivery vehicle is formed as a plurality of erodible microparticles or microcapsules which incorporate the compound of choice and are suspended in the nonaqueous liquid carrier.
  • mixtures of differing erodible microparticles and microcapsules can be combined in a single carrier within the scope of the present invention to tailor the pharmaceutical composition to specific drug contents, polymer erosion rates, and drug release profiles.
  • liquid carriers utilized in the pharmaceutical compositions of the present invention are particularly suitable for suspending polymeric drug delivery vehicles prepared with hydrolytically labile polymers or pharmaceutical compounds.
  • pharmaceutical compositions comprising hydrolytically stable polymeric drug delivery vehicles or pharmaceuticals are also within the scope of the present invention.
  • the pharmaceutical compositions of the present invention possess stable, long term shelf-lives without the associated loss of pharmaceutical activity of the therapeutic or diagnostic compound incorporated therein.
  • This stability results from the fact that the therapeutic or diagnostic compound does not leach or otherwise diffuse from the microparticulates or microcapsules into the liquid carrier, but remains incorporated in the drug delivery vehicle.
  • the microparticulates or microcapsules are formed of water labile polymers, they will not erode or degrade in the compositions of the present invention.
  • the pharmaceutical compositions of the present invention form low volume doses of less than 10 ⁇ l.
  • the pharmaceutical compositions of the present inven ⁇ tion preferably consisting of microparticulate or microcapsule drug delivery vehicles suspended in the liquid carriers, may be packaged and sterilized by conven ⁇ tional gamma irradiation techniques. Sterile fill proce ⁇ dures are available as an alternative to radiation sterilizing techniques.
  • the pharmaceutical compositions can be configured for multiple or unit dose packaging from, for example, a dropper dispenser.
  • the unique bacteriostatic properties of the liquid carriers further facilitate the utilization of multi-dose packaging by eliminating the necessity of preservative additives commonly used in the art.
  • compositions of the present invention can be utilized in forming the compositions of the present invention.
  • Polymers and agents which are hydrolytically labile are particularly suitable, however, ⁇ the advantageous properties of the nonaqueous compositions can be obtained with hydrolytically stable drug delivery vehicles as well.
  • FIG. 1 is a graphical representation of the release profile of sodium fluorescein from a microparticulate suspension stored at 23°C illustrating the principles of the present invention.
  • FIG. 2 is a graphical representation of the release profile of sodium fluorescein from a microparticulate suspension stored at 45°C illustrating the principles of the present invention.
  • FIG. 3 is a graphical representation of the temperature stability profile of a water labile drug containing microparticulate suspension stored at 37°C illustrating the principles of the present invention.
  • FIG. 4 is a graphical representation of the temperature stability profile of a water labile drug containing microparticulate suspension stored at 23°C illustrating the principles of the present invention.
  • the low volume, efficient pharmaceutical compositions of the present invention comprise one or more drug delivery vehicles suspended in a perfluorocarbon or fluorinated silicone nonaqueous liquid carrier.
  • the pharmaceutical compositions produced in accordance with the teachings of the present invention can be formed from a perfluorocarbon or fluorinated silicone liquid carrier and, suspended in the liquid carrier, at least one drug delivery vehicle incorporating a pharmaceutically effective amount of at least one therapeutic or diagnostic compound.
  • the pharmaceutical compositions formed in accordance with the teachings of the present invention are particularly well suited for use in connection with the diagnosis or treatment of injuries or diseases of the eye. Further advantages associated with their ophthalmic utility are the low surface tension and high density of the nonaqueous liquid carriers, which allow for small volume drop delivery. However, those skilled in the art will appreciate that the pharmaceutical compositions of the present invention are equally well suited for use in applications to other physiological environments where the repeated administration of a drug delivery vehicle to sensitive tissue areas is desired.
  • compositions of the present invention may be utilized through all common routes of administration such as oral, dermal, intravenous, nasal and others known in the art.
  • the perfluorocarbons which are preferably utilized as nonaqueous liquid carriers in the low volume, high efficiency pharmaceutical compositions of the present invention include perfluorocyclocarbons, acyclic perfluorocarbons and their derivatives.
  • the perfluorocarbon derivatives are typically nitrogen and oxygen containing compounds such as amines and ethers.
  • the nonaqueous liquid carrier compounds are preferably perfluorinated, meaning that all of the hydrogens bonded to the carbons of the compound are substituted with fluorine.
  • perfluo ⁇ rinated cyclic and acyclic hydrocarbons as well as the amine and ether derivatives of these compounds may be utilized in the pharmaceutical compositions of the present invention.
  • Perfluorocyclo- carbon blood substitutes include perfluorodecalin, perfluoroperhydrophenanthrene, perfluoromethylcyclohexane, p e r f l u o r o - l - m e t h y l d e c a l i n , p e r - f luoro(l, 3-dimethylcyclohexane) , perf luorotrimethylcyclo- hexane, perf luoroisopropylcyclohexane, perfluoro- e n d o t e t r a h y d r o d i c y c l o p e n t a d i e
  • Oxygen and nitrogen contain ⁇ ing derivatives of perfluorocarbons which may be used as liquid carriers include perfluorotributylamine, perfluorotriisopropylamine, perflubrotetrahydrofuran and perfluoroether.
  • Exemplary fluorinated silicone oils for use in practicing the present invention are the polyalkyl- fluoroalkylmethylsiloxanes.
  • the polytrifluoropropylmethylsiloxanes with molecular weights of between 500 and 14,000 are suitable for use in the pharmaceutical compositions of the present invention.
  • Preferred perfluorocarbarons and fluorinated silicones have vapor pressures sufficiently low to prevent significant liquid loss caused by their evaporation from containers during storage. Fluorinated liquid carriers having ambient pressure boiling points greater than 100°C are preferred to ensure that any evaporative losses are less than that observed for water.
  • exemplary preferred perfluorocarbons and fluorinated silicones have a rapid elimination half-life.
  • Perfluorodecalin PFD
  • PPP perfluoroperhydrophenanthrene
  • An additional aspect of the present invention involves suspending a polymeric drug delivery vehicle incorporating a pharmaceutically effective amount of at least one diagnostic or therapeutic compound in the perfluorocarbon or fluorinated silicone nonaqueous liquid carrier.
  • the polymeric drug delivery vehicle is in the form of a plurality of erodible microparticulates, each sized on the order of approxi ⁇ mately 2 microns to 200 microns or, alternatively, a plurality of microcapsules sized on the order of approxi ⁇ mately 20 microns to 200 microns.
  • larger drug delivery vehicles such as ocular inserts are also contemplated as being within the scope of the present invention.
  • compositions comprising a mixture of particle sizes or mixtures of microcapsules and microparticulates with varying erosion rates.
  • Such combinations can be designed to provide specific drug release profiles including high initial concentrations or so called zero order deliveries or may be utilized to provide combinations of different pharmaceutical compounds.
  • the solid or suspended drug delivery vehicles utilized in the pharmaceutical compositions of the present invention can be prepared through a variety of methods known to those skilled in the art. Exemplary methods for preparing microparticulates include grinding or milling mixtures of an appropriate polymer and therapeutic or diagnostic drug. Alternative methodologies include grinding or milling the polymer to form microparticulates and subsequently absorbing the drug of choice into the microparticulates so produced. Microencapsulation tech ⁇ niques in which emulsions of the polymer and therapeutic or diagnostic compound are coacervated to precipitate the polymer and encapsulate the compound also can be used to form microcapsule drug delivery vehicles for use in the present invention. Non-limiting examples of such formation techniques are provided below.
  • a general method for the manufacture of microparticulates involves the preparation of a stock polymer solution using 0-30% drug (preferably 0-10%) such as dipivefrin by first adding the drug to the solvent of choice such as acetone, acetonitrile, dimethylformamide, or ethyl acetate. The drug and solvent are combined and the mixture is stirred as the polymer (preferablypoly(methylvinylether/maleic anhydride) ) is added so polymer clumping is avoided. Mixing continues until the polymer is completely dissolved. The drug need not be completely dissolved in the solvent/polymer system, but the drug particles must be homogeneously dispersed. The mixture is then transferred to a roto-evaporator and the solvent is slowly removed.
  • drug preferably 0-10%
  • the solvent of choice such as acetone, acetonitrile, dimethylformamide, or ethyl acetate.
  • the polymer preferablypoly(methylvinylether/maleic anhydride
  • the temperature should not exceed 60°C.
  • the film is ground in the presence of dry ice with a small blade grinder until the appropriate sized range is achieved: 2-200 ⁇ m.
  • 5 g of poly(methylvinylether/maleic anhydride) is completely dissolved in a solution containing 100 mg dipivefrin in 95 ml of acetonitrile.
  • This polymer stock is then added to a roto- evaporator operating at 40°C, and the acetonitrile is completely removed.
  • the drug/polymer residue is removed from the evaporator flask and placed in a Teckmar grinder along with dry ice particles. The dry ice facilitates grinding, and the grinding takes approximately 2 minutes.
  • EXAMPLE 2 Alternatively, the drug/polymer stock mixture from Example 1 is roto-evaporated to dryness and the residue is first ground in a mortar and pestle and placed in a roller bottle containing glass beads with a nonaqueous diluent
  • the suspension is ball milled for approximately three days to reach the desired 2-200 ⁇ m size range.
  • EXAMPLE 3 Alternatively, the drug/polymer stock mixture from Example 1 is added dropwise with agitation to an immiscible liquid (preferably mineral oil) containing 0-10% emulsifier
  • Microparticles are formed as polymer stock is dispersed in the immiscible phase and the polymer solvent is evaporated.
  • Other immiscible liquids include vegetable oils, silicone oils, and perfluorocarbons.
  • the ratio of polymer stock solution to immiscible phase should not exceed 1:3 v/v.
  • the final particle size distribution of the particles is dependent on the degree of agitation and the viscosity of the immiscible material. Generally, a pneumatic mixer rotating at approximately 300 rpm gives the desired particle size range.
  • Exemplary polymers suitable for incorporating therapeutic or diagnostic compounds in accordance with the teachings of the present invention are those polymers which are compatible with both the target tissue and with the therapeutic or diagnostic compound of choice. Included within this class of polymers are both hydrolytically stable and hydrolytically labile polymers. Those skilled in the art, however, will appreciate that polymeric drug delivery vehicles prepared from polymers which are hydrolytically labile are particularly well suited for use with the perfluorocarbons or fluorinated silicone carriers of the present invention as they are stable in solution yet will erode in the aqueous environ ⁇ ment of the target site and thereby eliminate themselves from the site as their pharmaceutical compounds are delivered.
  • Exemplary hydrolytically stable polymers which are suitable for use in the polymeric drug delivery vehicles include acrylate, ethylene vinylacetate, silicones, polyurethanes, and polysulfone ⁇ .
  • Exemplary polymers which are labile in an aqueous environment include poly(methyl ⁇ vinylether/maleic anhydride) , polyfumaric acid/sebacic acid, collagen, gelatin, polyvinyl alcohol, methyl- celluloses, polyorthoesters, polyglycolic acid, polylactic acid, polyvinylpyrrolidone, polysebacic acid anhydride.
  • polycarboxyphenoxypropane anhydride, polyterephthalic acid anhydride, and polyphosphazine are examples of poly(methyl ⁇ vinylether/maleic anhydride) , polyfumaric acid/sebacic acid, collagen, gelatin, polyvinyl alcohol, methyl- celluloses, polyorthoesters, polyglycolic acid, polylactic acid, polyvinyl
  • a preferred exemplary aqueous labile polymer is Gantrez AN, a Poly(methylvinylether/maleic anhydride) available from GAF. Upon contact with an aqueous medium the anhydride functionalities of this polymer readily hydrolyze to form the free acid. This initial hydrolysis leads to the formation of a hydrogel with soft bioadhesive properties. As hydrolysis proceeds, the poly(methylvinylether/maleic anhydride) dissolves, and during the dissolution process the incorporated drug is continuously released.
  • pharmaceutical compositions prepared from Gantrez AN microparticulate or microcapsule drug delivery vehicles suspended in a perfluorocarbon carrier do not prematurely erode and release the incorporated drug. Similarly, they do not release the incorporated drug during storage and provide a long-shelf life, yet they are very effective when deliv- ered to the aqueous target environment.
  • An alternative hydrolytically labile polymer drug delivery system can be formed from those compounds which have ionic side chains capable of complexing with a drug of opposite ionic charge. Microparticulates formed of these polymers erode in the aqueous physiological environment and dissociate the drug which is ionically bound to the polymer thereby delivering the drug to the target site. Pharmaceutical compositions prepared from these ionic polymers suspended in " a nonaqueous carrier such as perfluorocarbon do not prematurely release the ionically bound drug and therefore can be prepared in stable, multi-dose forms.
  • a nonaqueous carrier such as perfluorocarbon
  • Any pharmaceutical compound which is suitable for therapeutic or diagnostic purposes and is compatible with a suitable polymer may be incorporated in the drug delivery vehicle of the present invention.
  • exemplary pharmaceutical compounds included protein growth factors. oligopeptides, antibacterial, antihistaminic, anti-inflammatory, iotic, anticoloneurgic, mydriatic, antiglaucoma, antiparisitic, antiviral, carbonic anhydrase inhibitor, antifungal, anesthetic, diagnostic and immunosuppressive agents.
  • Preferred pharmaceutical com ⁇ pounds for use in ocular situations include epithelial growth factor, dipivalyl epinephrine hydrochloride (DPE) , levo-bunolol hydrochloride, UK-14304-18, pilocarpine, dipivefrin, sodium fluorescein, tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, tobramycin, ciprofloxacin, norfloxacin, penicillin, erythromycin, cefazolin, ceftazidime, imipenem, idoxuridine, hydrocortisones, dexamethasone, dexamethasone 21 phosphate, fluocinolone, medrysone, prednisolone acetate, fluormetholone, betamethasone, trimeinolone, phenylephrine, eserine salicylate, carbachol, phospholine i
  • the amount of therapeutic or diagnostic compound incorporated in the polymer is dependent upon the compound of choice, the required dose, and the form of the drug delivery vehicle.
  • the effective amount normally ranges from a few percent up to 60% by weight of the polymer with microparticles generally having smaller amounts than microcapsules.
  • the pharmaceutical compositions may be prepared by methods known in the art for formulating drug delivery vehicles suspended in a liquid carrier.
  • the amount of drug delivery vehicle suspended in the carrier liquids of the present invention depends upon the dose configuration and the desired dose volume.
  • the volume ratio of carrier liquid to microparticulate ranges from about 99.0 to about 5.0.
  • Volume ratios for packaging configurations designed for multiple uses typically range from about 99.9 to about 3.0 liquid carrier to microparticulate.
  • the weight to volume ratio of suspended drug delivery vehicle to nonaqueous carrier liquid will range from approximately 0 to 10%.
  • the low volume, high efficiency pharmaceutical compositions of the present invention are finally packaged in sterile condition.
  • This may be achieved through formulation procedures utilizing sterile fill methods and heat or gamma irradiation techniques to obtain a sterile product.
  • One exemplary approach to producing a sterile pharmaceutical composition may be utilized when the desired microparticulate size is obtained with wet milling procedures utilizing a nonaqueous liquid carrier.
  • Such a procedure includes sterilizing the drug/polymer stock powder mixture using a suitable sterilizing method such as heat or gamma irradiation, and sterile filtering the selected perfluorocarbon or fluorinated silicone.
  • a suitable sterilizing method such as heat or gamma irradiation
  • sterile filtering the selected perfluorocarbon or fluorinated silicone The sterile drug/polymer stock powder is then aseptically combined with the sterile nonaqueous liquid carrier and the mixture is wet milled until the desired particle size is reached.
  • the final product is then aseptically filled into the desired package configuration.
  • Another procedure for obtaining sterile pharmaceutical compositions of the present invention includes dry milling drug/polymer stock to the desired particle size followed by sterilizing the resulting microparticulates.
  • the sterile dry powders are then aseptically added to a previously sterile filtered perfluorocarbon or fluorinated silicone.
  • the following additional non-limiting examples are illustrative of methods used for formulating the pharmaceutical compositions of the present invention.
  • microparticulate drug delivery vehicle suspended in a nonaqueous carrier the dry powder microparticulate drug delivery vehicles produced from the grinding procedure of the Example 1 are simply added to perfluorodecalin in a preferred ratio of from 0 to 10% w/v. Sonic agitation may be utilized to assist in the even distribution of the microparticulates.
  • the microparticulate drug delivery vehicle produced utilizing the ball milling procedure of Example 2 can be utilized as follows. As a preliminary step the drug containing microparticulates are separated from the glass beads of the ball mill. Where the nonaqueous diluent in the ball milling procedure is the preferred nonaqueous carrier liquid, such as perfluorodecalin the separated microparticulate suspension is simply diluted to the desired concentration, preferably ranging from approximately 0 to 10% w/v utilizing addition of perfluorodecalin. • As those skilled in the art will appreciate, where alternative grinding solvents are utilized additional separation may be necessary as is known in the art prior to preparing the suspension.
  • microparticulate drug delivery vehicles produced through the emulsion technique of Example 3 may be utilized to form the pharmaceutical compositions of the present invention as follows. Once the microparticulates produced through solvent evaporation are washed with the appropriate solvent, preferably hexane, the microparticulates are ' dried in a vacuum oven until all residual hexane is removed. The dried particles are simply added to perfluorodecalin or other nonaqueous carrier liquids in the desired proportions, preferably ranging from approximately 0 to 10% w/v.
  • surfactants and/or suspending agents in the pharmaceutical compositions.
  • the presence of surfactants or suspending agents assists in the formation of stable uniform suspension of microparticulates in perfluorocarbon or fluorinated silicones. Stable suspensions in turn contribute to the ability to deliver a consistent, low volume dose regimen over the life of the pharmaceutical composition.
  • Suitable exemplary pharmaceutically acceptable surfactants include non-ionic ethoxylated alcohols and sorbitans. Included in the group of acceptable surfactants are the Pluronics, Tweens, Polyethylene glycols, Spans, lecithin and oleic acid which act to neutralize residual static charges on the particles and to prevent aggregation.
  • Suspending agents include simple sugars, salts, synthetic polymers, polysaccharides and celluloses, etc., which act to prevent particle settling through steric collisions. Which suspending agents and surfactants are preferred will be dependent upon the particular polymer and perfluorocarbon or fluorinated silicone utilized routine in a specific pharmaceutical composition and can be determined utilizing stability testing procedures.
  • the exemplary perfluorocarbon and fluorinated silicone liquids utilized in the pharmaceutical compositions of the present invention provide unique chemical and physical properties which make them particularly well suited for use as nonaqueous liquid carriers for polymeric drug delivery vehicles. More particularly, they are chemically and physically stable.
  • drug delivery vehicles prepared from virtually any suitable polymer and drug combination may be suspended in the perfluorocarbon or fluorinated silicone liquid carriers for extended periods of time without unwanted interactions between the carrier and the polymer or drug.
  • the pharmaceutical compositions produced in accordance with the techniques of the present invention also have unexpectedly improved shelf-lives when compared with pharmaceutical compositions stored in a sterile, dry state. It is believed that the hydrophobic nature of the compositions precludes small amounts of oxygen and moisture from gaining access to the drug delivery vehicles, and thus they remain viable and pharmaceutically active for an extended period of time.
  • prior art drug delivery vehicles formed from hydrolytically labile polymers can not be suspended for long term storage in aqueous carriers. Normally, these vehicles are packaged and stored in the dry state in order to achieve reasonable shelf-lives. Users of drug delivery vehicles which are stored without the benefit of being suspended in a carrier liquid are inconvenienced by the necessity of having to suspend the vehicles in a sterile aqueous carrier just prior to delivery to the target site.
  • the perfluorocarbon or fluorinated silicone suspension vehicles utilized in the present invention provide a unique and advantageous alternative to storing labile microparticles or microcapsules in the dry state.
  • the pharmaceutical compositions prepared in accordance with the present invention are "user friendly" in that they are available in ready to use pre-mixed preparations.
  • an equally beneficial property of the pharmaceutical compositions of the present invention is their ability to remain stable for a long period of time without leaching or loss of the pharmaceutical compound from the polymeric drug delivery vehicle into the liquid carrier.
  • the pharmaceutical compounds are effectively locked in to the delivery vehicle until the formulation is administered to the desired physiological site.
  • the nonaqueous carrier solution is replaced by the aqueous physiological fluid at the target site which initiates release of the incorporated pharmaceutical compound.
  • This is specially important when the polymeric drug delivery vehicle utilized to form the pharmaceutical composition is a hydrolytically labile polymer.
  • hydrolytically labile polymers are characterized by their ability to physically or chemically erode in an aqueous environment.
  • This erosion occurs over a period of time by any of a number of different processes such as enzymatic degradation, hydrolysis, or solubilization in response to contact with an aqueous physiological environment.
  • a drug delivery vehicle which is formed from a hydrolytically labile polymer and an incorporated pharmaceutical compound is placed in the ocular environment, it erodes in a manner that results in the release or delivery of the drug to the eye.
  • the following examples are illustrative of the enhanced shelf life and prolonged stability of exemplary pharmaceutical compositions produced in accordance with the teachings of the present invention.
  • EXAMPLE 7 In order to determine the temperature stability and release profile of the nonaqueous drug delivery vehicle suspensions of the present invention microparticulates containing 5% sodium fluorescein were prepared utilizing poly(methylvinylether/maleic anhydride) as the polymer matrix utilizing the manufacturing technique of Example l and were suspended in perfluorodecalin as a 2% w/v suspension utilizing the technique of Example 4. This nonaqueous drug delivery vehicle suspension was divided in half and equal portions were stored at 23°C and at 45°C for thirty days. Samples were taken of each portion during the thirty day test period and fluorescein release profiles were obtained as is known in the art. More specifically, the dissolution tests were performed as follows.
  • EXAMPLE 8 An additional set of experiments was performed to determine if a water labile drug was stable in the suspended drug delivery vehicle when stored in the preferred nonaqueous carrier liquid, perfluorodecalin .
  • Microparticulates containing 2% dipivefrin were prepared from three different lots of poly(methylvinylether/maleicanhydride) obtained from GAF, Inc. (Lot #8277, 8555, and 8609) utilizing the microparticulate production technique of Example 1. The ground microparticulates were added to perfluorodecalin to form a 5% w/v suspension. As with Example 7, portions of this suspension were stored at different temperatures for thirty days. One portion was stored at 23°C (essentially ambient temperature) and a second portion at 37°C.
  • the nonaqueous liquid carriers utilized to form the low volume pharmaceutical compositions of the present invention are soothing, non- irritating and non-toxic.
  • their use in physiological applications, and in particular the ocular environment, is particularly suitable.
  • the experiment described in Example 9 illustrates and confirms this non- toxicity of an exemplary pharmaceutical composition of the present invention.
  • AN169 (a polyvinylether maleic anhydride) were prepared and suspended in perfluorodecalin. Two suspensions were studied, the first contained 2 w/v% microparticulate in perfluorodecalin and the second contained 5 w/v% microparticulate in perfluorodecalin. Because Gantrez AN169 is water labile, no comparable study in an aqueous suspension was possible. Each suspension was administered to rabbit eyes and no adverse effects were observed.
  • the pharmaceutical compositions of the present invention can be packaged for multi or single dose use.
  • the availability of the option for multi-dose packaging is a significant advantage over single dose or unit dose packaging which is required for many pharmaceutical compositions.
  • Single dose packing is more costly and many users prefer the convenience of, for example, large volume eye dropper delivery designs for multi-dose applications.
  • the pharmaceutical compositions of the present invention have bacteriostatic properties. These bacteriostatic properties make it possible to provide pharmaceutical compositions without preservative additives and the possible side effects thereof. This is particularly advantageous for users of ophthalmic preparations who have a sensitivity to preservatives. Additionally, when the pharmaceutical compositions of the present invention are packaged in multi-dose configurations they can be sterilized once and then repeatedly opened and reused without fear of the subsequent growth of harmful organisms in the liquid carrier. Other beneficial characteristics of the pharmaceutical compositions of the present invention derive from their ability to operate in the ocular environment with minimal vision disruption.
  • the nonaqueous carriers utilized in the pharmaceutical compositions have refractive indices which are very close to that of water. What is more, they are immiscible with both the lipid layer and the aqueous layer of the ocular tear film. This immiscibility reduces disruptive interac ⁇ tion with the tear film layers. Additionally, the advantageously small drop size and nearly identical refractive indices of the nonaqueous compositions and the aqueous layer of the tear film substantially eliminates the vision perturbation commonly associated with the use of current nonaqueous pharmaceutical carriers such as mineral oils.
  • the preferred perfluorocarbon carriers have specific gravities in excess of 1.2.
  • this relatively high specific gravity coupled with the carriers' immiscibility with the aqueous layer of the tear film, causes the carrier to separate rapidly from the particulate vehicle and to drain from the eye- through the lacrimal duct while leaving the slow release carrier in the intended aqueous environment.
  • the pharmaceutical composition so produced may be utilized to deliver therapeutic or diagnostic agents to physiological target sites including the eye or other similar environments through any currently available administration route.
  • An exemplary method for delivering therapeutic or diagnostic compounds comprises the steps of providing a pharmaceutical composition of a perfluorocarbon liquid carrier and at least one therapeutic or diagnostic drug containing delivery vehicle suspended therein and administering a low volume yet effective dosage of the pharmaceutical composition to the target site.
  • the administration route can be through injection, oral ingestion, nasal inhalation, topical application, eye drops or any other currently available administration route due to the broad applicability of the compositions of the present invention.
  • the beneficial delivery characteristics of the low volume, high efficiency pharmaceutical compositions of the present invention are produced by the physical properties of the fluorinated liquid carriers. More specifically, the high densities (typically greater than 1.2) and low surface tensions of perfluorocarbons and fluorinated silicones allow users to deliver dose volumes as low as 8 ⁇ l from standard dropper delivery systems.
  • the human ocular tear film is capable of accommodating volumes of only about 7 ⁇ l. Thus, the ability to deliver small volumes to the eye results in little or no costly loss of drugs which are largely blinked away when the prior art 35 ⁇ l - 50 ⁇ l volume oil and water liquid carrier delivery compositions are utilized to deliver pharmaceutical agents to the eye.
  • the present invention provides pharmaceutical compositions in the form of highly efficient, low dose volume, drop instillable mixtures of a nonaqueous physiologically acceptable perfluorocarbon liquid carrier and at least one drug polymeric delivery vehicle incorporating a pharmaceutically effective amount of a therapeutic or diagnostic compound.
  • the low dose volumes are preferably less than 10 ⁇ l.
  • the low dose volume, drop instillable mixtures are produced in the form of liquid suspensions of at least one polymeric drug delivery vehicle suspended in perfluorocarbon liquid carrier.
  • the preferred dose configuration of the pharmaceutical compositions of the present invention include a plurality of polymeric drug delivery vehicles in the form of microparticulates suspended in a perfluorocarbon liquid carrier.
  • Table I illustrates the dramatic distinction between the physical characteristic of water and that of two perfluorocarbons, PFD and PPP.
  • the high density and remarkable low surface tension allows very small drop volumes to be formed with standard liquid droppers.
  • water is limited to forming drops in the range of 35 ⁇ l - 50 ⁇ l.
  • the compositions of the present invention can be utilized to form advantageously small eye drops with standard droppers.
  • the bioavailability of pharmaceutical compounds utilized in the low volume, high efficiency pharmaceutical compositions of the present invention is substantially higher than pharmaceutical compounds delivered in larger drop aqueous systems.
  • EXAMPLE 10 A comparison of the pharmokinetic and pharmacologic characteristics of pilocarpine suspended in the perfluorocarbon versus pilocarpine in an aqueous solution was conducted on rabbits. This study involved delivering an 8 ⁇ l dose of pilocarpine suspended in the perfluorocarbon to rabbits' eyes and a corresponding 35 ⁇ l dose of the aqueous pilocarpine solution. The amount of pilocarpine actually retained by the eye following delivery was quantitatively determined for both the perfluorocarbon based delivery and for the aqueous based delivery.

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Abstract

L'invention concerne des compositions pharmaceutiques non aqueuses destinées à être utilisées dans des systèmes physiologiques aqueux. Lesdites compositions contiennent des véhicules d'administration de médicament en suspension dans des excipients liquides non aqueux de perfluorocarbone ou de silicone fluoré. Lesdits véhicules d'administration de médicament suspendus peuvent être labiles ou stables dans l'eau et contenir des composés thérapeutiques ou diagnostiques qui restent stables et pharmaceutiquement efficaces sur de longues périodes. Lesdites compositions pharmaceutiques présentent une meilleure biodisponibilité et permettent d'administrer de faibles doses de médicament. De plus, elles sont telles que les composés thérapeutiques ou diagnostiques incorporés ne peuvent pas passer dans les excipients liquides, ce qui les rend particulièrement adaptés à l'emballage et l'administration en doses multiples.
PCT/US1993/002500 1992-03-19 1993-03-16 Compositions contenant un vehicule d'administration de medicament en suspension dans un liquide fluore non aqueux WO1993018748A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5874469A (en) * 1996-01-05 1999-02-23 Alcon Laboratories, Inc. Fluoroalkyl hydrocarbons for administering water insoluble or unstable drugs
EP0988061A1 (fr) * 1997-03-21 2000-03-29 Imarx Pharmaceutical Corp. Procedes d'administration d'agents bioactifs
WO2002032402A1 (fr) * 2000-10-13 2002-04-25 Cambridge Biostability Ltd. Composition et procede pour liquides injectables stables
EP1366758A1 (fr) * 2001-02-15 2003-12-03 Sanwa Kagaku Kenkyusho Co., Ltd. Nouvelles compositions ophtalmiques
EP1449523A1 (fr) * 2000-10-13 2004-08-25 Cambridge Biostability Ltd Composition et procédé pour liquides injectables stables
WO2007109530A1 (fr) * 2006-03-20 2007-09-27 Allergan, Inc. Compositions de cyclosporine a

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1984000686A1 (fr) * 1982-08-17 1984-03-01 Sun Tech Inc Emulsions de perfluorocarbone, leur preparation et leur utilisation en therapie
EP0322249A2 (fr) * 1987-12-22 1989-06-28 Yissum Research Development Company Of The Hebrew University Of Jerusalem Méthodes de préparation et compositions pharmaceutiques contenant des dérivés du collagène
WO1991018613A1 (fr) * 1990-06-01 1991-12-12 Research Corporation Technologies, Inc. Verres autoemulsifiants
WO1992005770A1 (fr) * 1990-09-27 1992-04-16 Allergan, Inc. Vehicules de liberation de medicaments en suspension dans un support perfluore non aqueux

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1984000686A1 (fr) * 1982-08-17 1984-03-01 Sun Tech Inc Emulsions de perfluorocarbone, leur preparation et leur utilisation en therapie
EP0322249A2 (fr) * 1987-12-22 1989-06-28 Yissum Research Development Company Of The Hebrew University Of Jerusalem Méthodes de préparation et compositions pharmaceutiques contenant des dérivés du collagène
WO1991018613A1 (fr) * 1990-06-01 1991-12-12 Research Corporation Technologies, Inc. Verres autoemulsifiants
WO1992005770A1 (fr) * 1990-09-27 1992-04-16 Allergan, Inc. Vehicules de liberation de medicaments en suspension dans un support perfluore non aqueux

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5874469A (en) * 1996-01-05 1999-02-23 Alcon Laboratories, Inc. Fluoroalkyl hydrocarbons for administering water insoluble or unstable drugs
EP0988061A1 (fr) * 1997-03-21 2000-03-29 Imarx Pharmaceutical Corp. Procedes d'administration d'agents bioactifs
EP0988061A4 (fr) * 1997-03-21 2002-05-02 Imarx Pharmaceutical Corp Procedes d'administration d'agents bioactifs
WO2002032402A1 (fr) * 2000-10-13 2002-04-25 Cambridge Biostability Ltd. Composition et procede pour liquides injectables stables
EP1449523A1 (fr) * 2000-10-13 2004-08-25 Cambridge Biostability Ltd Composition et procédé pour liquides injectables stables
EP1452171A2 (fr) * 2000-10-13 2004-09-01 Cambridge Biostability Ltd Suspensions liquides pharmaceutiques
EP1452171A3 (fr) * 2000-10-13 2004-11-10 Cambridge Biostability Ltd Suspensions liquides pharmaceutiques
EP1366758A1 (fr) * 2001-02-15 2003-12-03 Sanwa Kagaku Kenkyusho Co., Ltd. Nouvelles compositions ophtalmiques
EP1366758A4 (fr) * 2001-02-15 2005-07-20 Sanwa Kagaku Kenkyusho Co Nouvelles compositions ophtalmiques
WO2007109530A1 (fr) * 2006-03-20 2007-09-27 Allergan, Inc. Compositions de cyclosporine a

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